CC-401 Promotes β-Cell Replication via Pleiotropic Consequences of DYRK1A/B Inhibition
| Autor: | Hannah P. Moeller, Justin P. Annes, Mark Smith, Neali A Armstrong, Yassan Abdolazimi, Sooyeon Lee, Timothy M. Horton, Benjamin Yeh, David McCutcheon, Haixia Xu, Robert J. Nichols, Paul Allegretti, Aryaman Shalizi, Zhengshan Zhao |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adult Male medicine.medical_specialty Receptor Transforming Growth Factor-beta Type I Cell Cycle Proteins In Vitro Techniques Protein Serine-Threonine Kinases 03 medical and health sciences Endocrinology Internal medicine Insulin-Secreting Cells medicine Animals Humans Pyrazolones Receptor E2F Research Articles Cell Proliferation Glycogen Synthase Kinase 3 beta NFATC Transcription Factors Chemistry Kinase Forkhead Box Protein M1 JNK Mitogen-Activated Protein Kinases NFAT Kv Channel-Interacting Proteins Cell cycle Middle Aged Protein-Tyrosine Kinases Cell biology Rats Repressor Proteins 030104 developmental biology Trans-Activators Phosphorylation Female Signal transduction Cyclin-Dependent Kinase Inhibitor p27 Transforming growth factor Transcription Factors |
| Popis: | Pharmacologic expansion of endogenous β cells is a promising therapeutic strategy for diabetes. To elucidate the molecular pathways that control β-cell growth we screened ∼2400 bioactive compounds for rat β-cell replication-modulating activity. Numerous hit compounds impaired or promoted rat β-cell replication, including CC-401, an advanced clinical candidate previously characterized as a c-Jun N-terminal kinase inhibitor. Surprisingly, CC-401 induced rodent (in vitro and in vivo) and human (in vitro) β-cell replication via dual-specificity tyrosine phosphorylation–regulated kinase (DYRK) 1A and 1B inhibition. In contrast to rat β cells, which were broadly growth responsive to compound treatment, human β-cell replication was only consistently induced by DYRK1A/B inhibitors. This effect was enhanced by simultaneous glycogen synthase kinase–3β (GSK-3β) or activin A receptor type II–like kinase/transforming growth factor-β (ALK5/TGF-β) inhibition. Prior work emphasized DYRK1A/B inhibition–dependent activation of nuclear factor of activated T cells (NFAT) as the primary mechanism of human β-cell–replication induction. However, inhibition of NFAT activity had limited effect on CC-401–induced β-cell replication. Consequently, we investigated additional effects of CC-401–dependent DYRK1A/B inhibition. Indeed, CC-401 inhibited DYRK1A-dependent phosphorylation/stabilization of the β-cell–replication inhibitor p27(Kip1). Additionally, CC-401 increased expression of numerous replication-promoting genes normally suppressed by the dimerization partner, RB-like, E2F and multivulval class B (DREAM) complex, which depends upon DYRK1A/B activity for integrity, including MYBL2 and FOXM1. In summary, we present a compendium of compounds as a valuable resource for manipulating the signaling pathways that control β-cell replication and leverage a DYRK1A/B inhibitor (CC-401) to expand our understanding of the molecular pathways that control β-cell growth. |
| Databáze: | OpenAIRE |
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